ArticleDevelopment (Cambridge, England)2022
A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling.
Article in Development (Cambridge, England), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 37 citations in OpenAlex.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- CSF1R-related leukoencephalopathy: experimental models and potential for treatment.Disease models & mechanisms · 2026Review
- Depletion and replacement of tissue-resident macrophages in mice with germ-line deletion of a conserved enhancer in the Csf1r locus.Development (Cambridge, England) · 2026Article
- A strategy of microglia replacement alleviates microgliopathy in a CSF1R I794T hotspot mutation mouse model of CSF1R-related disorder.Cell reports. Medicine · 2026Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- Mutation in the rat interleukin 34 gene impacts macrophage development, homeostasis, and inflammation.Life science alliance · 2025Article
- Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity.Nature immunology · 2025Article
- Article
- Single-cell transcriptomics identify a novel macrophage population associated with bone invasion in pituitary neuroendocrine tumors.Journal of experimental & clinical cancer research : CR · 2025Article
- Non-Malignant Granulocyte and Monocyte Disorders: An Update.British journal of biomedical science · 2025Review
- Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy.Neuron · 2024Article
- Microglia in Health and Diseases: Integrative Hubs of the Central Nervous System (CNS).Cold Spring Harbor perspectives in biology · 2024Review
- Identification and characterization of a novel intronic splicing mutation in CSF1R-related leukoencephalopathy.CNS neuroscience & therapeutics · 2024Article
- Clinical, genetic, and molecular characteristics in a central-southern Chinese cohort of genetic leukodystrophies.Annals of clinical and translational neurology · 2023Article
- Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).Journal of neuroinflammation · 2023Article
- Article
- Dominant-acting CSF1R variants cause microglial depletion and altered astrocytic phenotype in zebrafish and adult-onset leukodystrophy.Acta neuropathologica · 2022Article
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22 authors at 8 institutions in 5 countries.
Funding
Abstract
Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.